The First Amendment may not protect someone yelling “Fire!” in a crowded theater, but should shield 23andMe and other direct-to-consumer (DTC) genetic testing companies from “overcautious” FDA regulation, two longtime supporters of test providers argue, reopening the debate over agency dealings with the company.

Robert C. Green, Ph.D., and Nita A. Farahany, Ph.D., J.D., urged FDA to avoid restricting consumer genomic testing “unless faced with empirical evidence of harm.” They cited two cases where courts used free-speech protection to overturn a law curbing the use of doctors’ prescription records, and a doctor’s conviction for promoting off-label drug use.

“As the court cases of Sorrell v. IMS Health (2011) and United States v. Caronia (2012) demonstrate, doing so could put FDA regulations in greater tension with the First Amendment,” Drs. Green and Farahany concluded.

The co-authors’ arguments, published in Nature, come about two months after FDA ordered 23andMe to stop selling its Saliva Collection Kit and Personal Genome Service (PGS), and obtain agency approval to market the $99 “spit kit.” The company still provides consumers ancestry-related information and raw genetic data without interpretation, uses its database of genetic and phenotypic data in research, and maintains educational efforts.

While FDA considers the PGS a medical device requiring agency approval, the test is designed to provide interpretations about common genetic variants that 23andMe says are meant to provide users with deeper insights into their ancestry and inherited traits, not a diagnosis.

That lack of diagnostic analysis was faulted last month in an adverse-event report filed with FDA by an unidentified user who criticized the PGS for lack of information about a colorectal cancer mutation that led the person to undergo a colonoscopy and barium enema. 23andMe won’t comment on the case, in which the mutation turned up in raw data but not a genetic report. The variant either hasn’t been curated by 23andMe, or may not meet its criteria for inclusion in reports, such as 98%+ reliability and availability of published research.

Dr. Green is associate director for research at Partners HealthCare Center for Personalized Genetic Medicine, and an associate professor at Brigham and Women’s Hospital and Harvard Medical School. Dr. Farahany is a professor at Duke University School of Law and Duke Institute for Genome Sciences and Policy.

Drs. Green and Farahany cited several studies concluding that DTC testing results had not plunged large percentages of customers into despair or panicked them to visit their doctors.

In the Scripps Genomic Health Initiative (SGHI) launched in 2009, 2,037 participants showed no significant differences in anxiety, diet, or exercise at a mean 5.6 months after testing with Navigenics’ Health Compass. The Impact of Personal Genomics (PGen) Study, co-led by Dr. Green, yielded preliminary data on 1,800 23andMe and Pathway Genomics customers surveyed in 2012–13. That data suggested customers never showed heightened anxiety or distress over the following year. And an earlier Johns Hopkins survey showed just over one-quarter of more than 1,000 DTC testing customers shared results with physicians a few months after receiving them.

Partial Negation

Full PGen results are expected this year. Should PGen and other studies confirm low incidence of anxiety or medical action from DTC testing results, would that negate the need for more FDA regulation?

“I think it would partially negate the need for regulation because it would suggest that very few customers operate entirely on their own without medical supervision,” Dr. Green told GEN on Wednesday. “However, other concerns would remain, such as whether such testing was likely to drive up medical costs (and possibly iatrogenic tests and procedures) without making significant improvements in health outcomes.”

He and Dr. Farahany were blunter in their article: “The FDA’s precautionary approach may pose a greater threat to consumer health than the harms that it seeks to prevent.”

Not so, says Jeremy Gruber, J.D., president and executive director of the Council for Responsible Genetics, whose board includes Dr. Green.

“The ‘harm’ that the authors dispute and focus on—that a person might take drastic action as a result of getting a test—is the wrong emphasis,” Gruber told GEN. He cited an October 30 American Journal of Psychiatry study (Lineweaver, et. al., 2013), where participants who were told they carry a gene variant predisposing them to Alzheimer’s disease did worse cognitively than variant carriers who weren’t told.

“The ‘harm’ occurs not only when an adverse action is taken, but far more broadly when a consumer is unable to make an informed choice about purchasing the product in the first place because the corporate claims about the product exaggerate its utility,” Gruber said. “23andMe, and the DTC industry more generally, have been aware over concerns of accuracy and exaggerated claims for years and have failed to act. That is precisely why regulators are stepping in: to protect consumers from an industry unwilling to police itself.”

Seeking More Transparency

Acknowledging longstanding concerns, Drs. Farahany and Green added: “We believe that 23andMe should be more transparent about how accurate its genotyping chips are, and even more forthcoming about the limitations of its computer algorithms used for estimations of risk.”

Speaking with GEN, Dr. Green said 23andMe was among DTC companies that are very transparent about the algorithms themselves.

“What we actually meant to be calling for was more transparency about the uncertainty that is inherent in their algorithms, making it clear to customers that there are various ways to calculate risk that give different answers and that theirs (though transparently available in the form of a white paper on the site and actually quite reasonable) is only one such way and has not been proven to be ‘correct’,” Dr. Green added.

DTC test providers are unlikely to favor full disclosure, and neither is FDA—whose business-friendliness already includes shielding from public review details of pending drug applications.

“We do have to look for ways to enhance transparency about our service that don’t compromise privacy, security, or proprietary information. There is a bit of a balance needed,” 23andMe spokeswoman Catherine Afarian told GEN.

To the extent companies have data they don’t want public for business, privacy or security reasons, Afarian added, “regulation has an important role, because it can really help people with confidence in a new and growing industry—not just 23andMe, but the genetics industry much more broadly.”

“Appropriate” Paths

Neither Afarian nor FDA spokeswoman Susan Laine would discuss details of the company’s dealings with the agency since its November 22 warning letter. “FDA’s intent has always been to help the company find the best path forward for their device,” Laine told GEN.

“The agency, along with many others, recognizes that innovation requires validation, and has worked not only with 23andMe, but with other companies with innovative products, to define appropriate paths and data requirements for regulatory authorization,” Laine said. She cited FDA’s approval in November of Illumina’s MiSeqDx™ next-gen DNA sequencing analyzer—the first to win FDA clearance—plus two cystic fibrosis assays and a library preparation kit.

In 2011, by contrast, an FDA panel “generally agreed” on a key role for doctors that included advising consumers about their results after exclusively offering several categories of tests. “Those categories include presymptomatic tests with high predictor for a disease, with potentially severe consequences, and pharmacogenetic tests,” the FDA Molecular & Clinical Genetics Panel said.

FDA never translated the panel’s recommendation into policy.

“Requiring a physician/genetic counselor to provide DTC data does add an extra layer of protection for the patient since the data would only be given to the patient by a qualified medical professional who can provide context and a level of interpretation,” Colleen M. Heisey, J.D., a partner with the law firm Jones Day, told GEN. “However, this may also be burdensome for patients and they may hesitate to take advantage of useful information regarding their health.”

“For the practitioner, risks include whether and how they interpret and explain results, whether they are relying on appropriate tests or test providers, etc., similar to current practice management relating to any test results,” Dr. Heisey added.

The risks cited by Dr. Heisey likely explain why the agency retreated from that path. Indeed, the silence may be the story: The agency’s noisy rhetoric has given way to a revived review of 23andMe’s PGS that will also likely yield some form of approval. Until then, no news is good news for 23andMe.

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